Erythrocyte n-6 Polyunsaturated Fatty Acids, Gut Microbiota, and Incident Type 2 Diabetes: A Prospective Cohort Study

Abstract

Objective: To examine the association of erythrocyte n-6 polyunsaturated fatty acid (PUFA) biomarkers with incident type 2 diabetes and explore the potential role of gut microbiota in the association.

Research design and methods: We evaluated 2,731 participants without type 2 diabetes recruited between 2008 and 2013 in the Guangzhou Nutrition and Health Study (Guangzhou, China). Case subjects with type 2 diabetes were identified with clinical and biochemical information collected at follow-up visits. Using stool samples collected during the follow-up in the subset (n = 1,591), 16S rRNA profiling was conducted. Using multivariable-adjusted Poisson or linear regression, we examined associations of erythrocyte n-6 PUFA biomarkers with incident type 2 diabetes and diversity and composition of gut microbiota.

Results: Over 6.2 years of follow-up, 276 case subjects with type 2 diabetes were identified (risk 0.10). Higher levels of erythrocyte γ-linolenic acid (GLA), but not linoleic or arachidonic acid, were associated with higher type 2 diabetes incidence. Comparing the top to the bottom quartile groups of GLA levels, relative risk was 1.72 (95% CI 1.21, 2.44) adjusted for potential confounders. Baseline GLA was inversely associated with gut microbial richness and diversity (α-diversity, both P < 0.05) during follow-up and significantly associated with microbiota β-diversity (P = 0.002). α-Diversity acted as a potential mediator in the association between GLA and type 2 diabetes (P < 0.05). Seven genera (Butyrivibrio, Blautia, Oscillospira, Odoribacter, S24-7 other, Rikenellaceae other, and Clostridiales other) were enriched in quartile 1 of GLA and in participants without type 2 diabetes.

Conclusions: Relative concentrations of erythrocyte GLA were positively associated with incident type 2 diabetes in a Chinese population and also with gut microbial profiles. These results highlight that gut microbiota may play an important role linking n-6 PUFA metabolism and type 2 diabetes etiology.

Figure 1

Erythrocyte GLA and gut microbiota covary in the development of type 2 diabetes risk. A: Community richness (observed OTUs and Chao index) and community diversity (Shannon diversity index and Simpson index) between Q1 and Q4 of erythrocyte GLA. The box plots feature the median (center line), upper and lower quartiles (box limits), and 1.5 times the interquartile range (whiskers). P values were calculated for Q4 of the erythrocyte n-6 fatty acids using Q1 as the reference group using a linear mixed model. B: Community richness (observed OTUs and Chao index) and community diversity (Shannon diversity index and Simpson index) across type 2 diabetes status. P values were calculated using a logistic regression model. C: Dissimilarities in gut microbiota composition between Q1 and Q4 of erythrocyte GLA represented by unconstrained principal coordinate analysis (PCoA) with the Bray Curtis dissimilarity index. Difference of erythrocyte GLA explained 0.3% of the dissimilarities in gut microbiota composition (PERMANOVA, P = 0.006). D: Dissimilarities in gut microbiota composition across type 2 diabetes status. Type 2 diabetes explained 0.25% of the dissimilarities in gut microbiota composition (PERMANOVA, P = 0.001). E: Gut microbial taxonomic biomarkers identified by the LDA at Q1 and Q4 of erythrocyte GLA and by type 2 diabetes status. T2D, patients with type 2 diabetes; Non-T2D, participants without type 2 diabetes.

Figure 2

Heat map of the Spearman correlation coefficients between GLA-related microbes and 10 type 2 diabetes–related traits. The intensity of the colors represents the degree of association between GLA-related microbes and 10 type 2 diabetes–related traits as measured by the Spearman correlations. All significant correlations are marked with an asterisk (Bonferroni-corrected P < 0.05). HOMA-β, HOMA of β-cell function; HOMA-IR, HOMA of insulin resistance; TC, total cholesterol; TG, triglycerides.